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Fluorinated Analog NMR S of Organosulfur Compounds from Garlic (Allium Sativum): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies

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Fluorinated Analog NMR S of Organosulfur Compounds from Garlic (Allium Sativum): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies molecules Article Fluorinated Analog NMR s of Organosulfur Compounds from Garlic (Allium sativum): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies Eric Block 1,* ID , Benjamin Bechand 1, Sivaji Gundala 1, Abith Vattekkatte 1, Kai Wang 1, Shaymaa S. Mousa 2, Kavitha Godugu 2, Murat Yalcin 2,3 and Shaker A. Mousa 2,* ID 1 Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222, USA; [email protected] (B.B.); [email protected] (S.G.); [email protected] (A.V.); [email protected] (K.W.) 2 The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA; [email protected] (S.S.M.); [email protected] (K.G.); [email protected] (M.Y.) 3 Department of Physiology, Veterinary Medicine Faculty, Uludag University, Bursa 16059, Turkey * Correspondence: [email protected] (E.B.); [email protected] (S.A.M.); Tel.: +1-518-442-4459 (E.B.); +1-518-694-7397 (S.A.M.) Received: 6 October 2017; Accepted: 24 November 2017; Published: 28 November 2017 Abstract: We describe the synthesis, reactivity, and antithrombotic and anti-angiogenesis activity of difluoroallicin (S-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate) and S-2-fluoro-2-propenyl-L- cysteine, both easily prepared from commercially available 3-chloro-2-fluoroprop-1-ene, as well as the synthesis of 1,2-bis(2-fluoroallyl)disulfane, 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin, trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane), and a bis(2-fluoroallyl)polysulfane mixture. All tested organosulfur compounds demonstrated effective inhibition of either FGF or VEG-mediated angiogenesis (anti-angiogenesis activity) in the chick chorioallantoic membrane (CAM) or the mouse Matrigel® models. No embryo mortality was observed. Difluoroallicin demonstrated greater inhibition (p < 0.01) versus organosulfur compounds tested. Difluoroallicin demonstrated dose-dependent inhibition of angiogenesis in the mouse Matrigel® model, with maximal inhibition at 0.01 mg/implant. Allicin and difluoroallicin showed an effective antiplatelet effect in suppressing platelet aggregation compared to other organosulfur compounds tested. In platelet/fibrin clotting (anti-coagulant activity), difluoroallicin showed concentration-dependent inhibition of clot strength compared to allicin and the other organosulfur compounds tested. Keywords: garlic; allicin; vinyl dithiins; ajoene; difluoroallicin; trifluoroajoene; angiogenesis; anti-angiogenesis; platelet; coagulation; thrombosis; anti-thrombotic; 2-fluoroallyl sulfur compounds 1. Introduction Since its discovery by Cavallito in 1944, the antibiotic active principle of garlic, allicin (1), has been the subject of extensive research [1–3]. Enzymatically released from its precursor alliin (2) when garlic is crushed, allicin is both unstable and reactive, readily decomposing by way of 2-propenesulfenic acid (3) and thioacrolein (5) to diallyl disulfide (4) and homologous polysulfides (polysulfanes), vinyl 1,2- and 1,3-dithiins (6 and 7, respectively) and ajoene (8) (Scheme1), among other products, all of which have interesting biological properties, e.g., as antiplatelet and anticancer agents [1–8]. Given the great importance of fluorine in medicinal chemistry and chemical biology [9,10], we were interested in Molecules 2017, 22, 2081; doi:10.3390/molecules22122081 www.mdpi.com/journal/molecules Molecules 2017, 22, 2081 2 of 20 [9,10], we were interested in the effect that fluorine substitution would have on the chemical reactivity and biological activity of these compounds, since such fluorinated analogs are presently unknown. Compounds with C–F bonds, particularly of the sp2-C–F type, offer advantages associated with the small size, high electronegativity, and metabolic stability associated with the fluorine as well as the altered molecular lipophilicity, membrane fluidity, binding affinity, enhanced volatility, and possibilities for halogen bonding [11] and conformational preferences of the fluorinated compounds compared to their hydrogen analogs. We also follow up on our previous work on trifluoroselenomethionine [12]. Thiol group reactivity, a defining feature of the biological activity of allicin and other garlic compounds [13–15], should be enhanced by H/F substitution in garlic thioallyl compounds. Three types of C–F substituted allyl groups were considered for this study, namely CH2=CFCH2– X (A), CF2=CFCH2–X (B), and CF2=CFCF2–X (C). We chose type A based on commercial availability of CH2=CFCH2Cl (3-chloro-2-fluoroprop-1-ene (9) (Scheme 2), as well as on our inability to convert thioacetate CF2=CFCH2SAc (from Mitsunobu reaction of CF2=CFCH2OH [16]) to the corresponding disulfide, and on the relative inaccessibility of precursors C, such as CF2=CFCF2OSO2F [17]. Here, we describe our efforts to synthesize and study the reactivity and activity of difluoroallicin 12 (S-(2- fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate), easily prepared from 9, and related compounds such as S-2-fluoro-2-propenyl-L-cysteine (fluorodeoxyalliin, 13), 1,2-bis(2-fluoroallyl)disulfane (11), 5- Molecules 2017, 22, 2081 2 of 20 fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin (16), trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoro- allyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane, 18), and 1,2-bis(2-fluoroallyl)polysulfane (21). Wethe effectalso describe that fluorine the anti-angiogenesis substitution would and haveantithro on thembotic chemical activity reactivity of some andof these biological compounds. activity of theseCancer compounds, progression since such is known fluorinated to be analogsaccelerated are presentlyby angiogenesis unknown. and Compounds thrombosis with(platelet/fibrin) C–F bonds, particularlystimulation, ofwhich the sp in2-C–F turn type, are offermediated advantages by vari associatedous factors with secreted the small by size, cancer high cells electronegativity, [18–20]. We previouslyand metabolic showed stability that garlic-derived associated with bioactive the fluorine compounds as well modulate as the altered angiog molecularenesis [5], which lipophilicity, might impactmembrane cancer fluidity, progression binding affinity,and suggests enhanced potent volatility,ial cancer and possibilitieschemoprevention for halogen by organosulfur bonding [11] compounds,and conformational as we further preferences examine of the in fluorinated this study. compounds Additionally, compared studies tosuggest their hydrogenpotential analogs.platelet Wefunction also followmodulation up on by our garlic previous derived work bioactive on trifluoroselenomethionine compounds [21,22]. Our [12 current]. Thiol studies group compared reactivity, thea defining efficacy feature of fluorinated of the biological and non-fluorinated activity of allicin organosulfur and other compounds garlic compounds on angiogenesis [13–15], shouldactivation be byenhanced either bFGF by H/F or VEGF substitution as well in as garlic their thioallylcomparative compounds. efficacy on platelet and coagulation activation. Scheme 1. EnzymaticEnzymatic formation formation of of allicin allicin ( (11)) from from alliin alliin ( (22)) by by way of 2-propenesulfenic2-propenesulfenic acid acid ( (3),), synthesis of allicin by oxidation of diallyl disulfide disulfide ( 4), conversion of 1 to ajoene ( 8), and decomposition of 1 toto vinyl vinyl dithiins dithiins ( (66 andand 77)) via via intramolecular intramolecular elimination elimination to to thioacrolein thioacrolein (5 ().5 ). Three types of C–F substituted allyl groups were considered for this study, namely CH2=CFCH2–X (A), CF2=CFCH2–X (B), and CF2=CFCF2–X (C). We chose type A based on commercial availability of CH2=CFCH2Cl (3-chloro-2-fluoroprop-1-ene (9) (Scheme2), as well as on our inability to convert thioacetate CF2=CFCH2SAc (from Mitsunobu reaction of CF2=CFCH2OH [16]) to the corresponding disulfide, and on the relative inaccessibility of precursors C, such as CF2=CFCF2OSO2F[17]. Here, we describe our efforts to synthesize and study the reactivity and activity of difluoroallicin 12 (S-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate), easily prepared from 9, and related compounds such as S-2-fluoro-2-propenyl-L-cysteine (fluorodeoxyalliin, 13), 1,2-bis(2-fluoroallyl)disulfane (11), 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin (16), trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane, 18), and 1,2-bis(2- fluoroallyl)polysulfane (21). We also describe the anti-angiogenesis and antithrombotic activity of some of these compounds. Cancer progression is known to be accelerated by angiogenesis and thrombosis (platelet/fibrin) stimulation, which in turn are mediated by various factors secreted by cancer cells [18–20]. We previously showed that garlic-derived bioactive compounds modulate angiogenesis [5], which might impact cancer progression and suggests potential cancer chemoprevention by organosulfur compounds, as we further examine in this study. Additionally, studies suggest potential platelet function modulation by garlic derived bioactive compounds [21,22]. Our current studies compared the efficacy of fluorinated and non-fluorinated organosulfur compounds on angiogenesis activation by either bFGF or VEGF as well as their comparative efficacy on platelet and coagulation activation. Molecules 2017, 22, 2081 3 of 20 Molecules 2017, 22, 2081 3 of 20 SchemeScheme 2. Synthesis 2. Synthesis of of difluoroallicin difluoroallicin (12)) from
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